Fas (also called CD95 and APO-1) is a prototypical death receptor that regulates tissue homeostasis primarily in the immune system through induction of apoptosis. During cancer progression, Fas is frequently downregulated, or cells are rendered apoptosis resistant, raising the possibility that loss of Fas is part of a mechanism for tumor evasion. However, complete loss of Fas is rarely seen in human cancers and many cancer cells may express large quantities of Fas, and are highly sensitive to Fas mediated apoptosis in vitro. Furthermore, cancer patients frequently have elevated levels of the physiological ligand for Fas, FasL. These data raised the intriguing possibility that Fas might actually promote the growth of tumors through its nonapoptotic activities. Our recent data have confirmed that cancer cells in general, regardless of their Fas apoptosis sensitivity, depend on constitutive activity of Fas and expression of FasL for optimal growth and survival. Consistently, loss of Fas in mouse models of ovarian cancer and liver cancer prevents or reduces cancer formation, and elimination of FasL in cancer cells causes them to die. Based on these data we propose to study three specific aims: Specific Aim 1: Determine the role of Fas/FasL for the growth and survival of cancer cells. Hypothesis: Fas is a general tumor promoting receptor through a basal activity which involves JNK1 induced AP-1 driven proliferation, and this activity is essential for cancer cell survival. Specific Aim 2: Explore the connection between Fas and energy metabolism. Hypothesis: Regulation of energy metabolism by Fas and FasL is required for tumor cells to grow. Specific Aim 3: Establish preclinical models for the treatment of cancer by blocking the activity of FasL. Hypothesis: Inhibition of FasL rather than the activation of Fas can be used to treat ovarian and liver cancer. The results of this proposal will help delineate the novel activities of Fas as a tumor promoter and are expected to result in a clinically relevant and novel approach to treating cancer. PUBLIC HEALTH RELEVANCE: The apoptosis-inducing Fas and its ligand FasL have recently been recognized to mediate nonapoptotic signaling in tissues and tumor cells. Especially in the context of ovarian and liver cancer it has become clear that these activities contribute to cancer formation and growth. In this proposal we will characterize these novel activities which should be highly relevant for therapy resistance in cancer patients and establish preclinical mouse models to block these tumorigenic activities of Fas using a soluble Fas receptor.